All drugs contain various levels of related substances in addition to the active ingredient. The identities and amounts of the related substances depend upon the way in which the drug has been manufactured. Thus different manufacturing processes afford different forms of a drug.
Nizatidine is the generic name for a drug the active ingredient of which is N-[2-[[[2-[dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl-N'-methyl-2 -nitro-1,1-ethenediamine. The compound is a histamine H.sub.2 -receptor antagonist which is used in the treatment of duodenal ulcers and other gastrointestinal disorders.
Processes for preparing nizatidine have been disclosed in U.S. Pat. Nos. 4,587,344, 4,777,260; 4,904,792 and 5,334,725. These processes all involve compounds which produce strong and unpleasant odors. The final stages of the processes disclosed in U.S. Pat. Nos. 4,904,792 and 5,334,725 both involve the same reaction of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine with N-methyl-1-methylthio-2-nitroethyleneamine. The examples illustrate the use of water as reaction solvent. The final stage of the process disclosed in U.S. Pat. No. 4,587,344 involves the reaction of N-methyl-S-methyl-N'-[2-(2-dimethylaminomethylthiazol-4-ylmethylthio)ethyl isothiourea with nitromethane. Each of the final stages of the processes disclosed in U.S. Pat. Nos. 4,904,272, 5,334,725 and 4,857,344 involves the production of methanethiol, which has a particularly unpleasant sulfur-like odor. The final stage of the process disclosed in U.S. Pat. No. 4,777,260 involves the reaction of N-[2-[[[2-(dimethylamino)-methyl]-4-thiazolyl]methyl]thio]ethyl-2-nitro-1- phenoxy-1-etheneamine with methylamine. This reaction does not involve the formation of methanethiol.
It will be appreciated that each of the forms of nizatidine prepared by each of the different processes is different, because of the different residual substances present.
Pharmaceutical compositions of nizatidine are presently sold in gelatin capsules under the trade mark AXID (AXID is a registered trademark of Eli Lilly and Company). The capsules emit a characteristic sulfur-like odor. This odor is referred to in package inserts accompanying the capsules and also in physicians manuals, for example the Physician's Desk Reference, 48th Edition, 1994, page 1208, published by Medical Economics Data Production Company at Montvale, N.J. 07645-1742, United States.
It has now been found that the source of the odor of the commercially available gelatin capsules containing nizatidine is not the active ingredient, but a trace related substance in the drug, N-methyl-1-methylthio-2-nitroethyleneamine. This is one of the starting materials in the process for preparing nizatidine disclosed in U.S. Pat. Nos. 4,904,792 and 5,344,725. The nizatidine present in the commercial formulation has been found typically to contain about 150 ppm of this related substance.
It has also been found that N-methyl-1-methylthio-2-nitroethyleneamine may be removed from nizatidine containing N-methyl-1-methylthio-2-nitroethyleneamine by heating said nizatidine containing N-methyl-1-methylthio-2-nitroethyleneamine in water at an elevated temperature.
Without wishing to be bound by theory, it is believed that the odor of the commercially available gelatin capsules results from a reaction, catalysed by the active ingredient, between N-methyl-1-methylthio-2-nitroethyleneamine and water present inside: the capsule. The reaction affords methanethiol, which oxidises in air to afford dimethyldisulfide, and it is this substance that is responsible for the odor.